ESMO 2025 Novel T-cell therapy shows promise in uveal melanoma

medwireNews: The PRAME-directed T-cell receptor (TCR) T-cell therapy anzutresgene autoleucel (anzu-cel) has shown encouraging tolerability and antitumor activity in people with previously treated locally advanced or metastatic uveal melanoma in a phase 1 study.

“PRAME is an intracellular protein” that is expressed in approximately 90% of patients with uveal melanoma, explained researcher Sapna Patel (University of Colorado, Aurora, USA) at a Presidential Session of the ESMO Congress 2025 in Berlin, Germany.

“It’s processed into peptides and then taken to the cell surface in the context of an HLA molecule,” she said, further explaining that “the investigational product – anzu-cel or IMA203 – is a T cell transduced with a receptor that recognizes this HLA/PRAME complex.”

In the trial, patients with locally advanced or metastatic solid tumors that were positive for both HLA-A*02:01 and PRAME underwent leukapheresis, followed by anzu-cel manufacture over a 2-week period. After lymphodepletion, they received a single infusion of anzu-cel supported by 10 days of low-dose interleukin-2.

The current presentation focused on the 16 patients with uveal melanoma, who received a median TCR T-cell dose of 3.94x10⁹ cells. They were aged a median of 62 years, nearly two-thirds (63%) were women, and the majority (81%) had both liver and extrahepatic metastases. The participants had received a median of two prior systemic therapies, 63% had received prior tebentafusp, and all had received liver-directed therapies.

Safety of anzu-cel in uveal melanoma is generally as expected

Patel reported that the most common treatment-emergent adverse events were cytopenias, noting that “these were expected from the lymphodepleting chemotherapy regimen.” Specifically, grade 3–4 neutropenia occurred in 94% of patients, while anemia, thrombocytopenia, leukopenia, and lymphopenia occurred in 50%, 38%, 38%, and 25%, respectively.

All patients experienced cytokine release syndrome (CRS) but just 19% were of grade 3 and there were no grade 4 or 5 events. The median duration was 9 days and “most CRS had resolved by day 14 and no long-term CRS was seen,” noted the presenter.

She added that there were no grade 5 adverse events related to anzu-cel in either the 16 patients with uveal melanoma or the wider trial population.

Anzu-cel has promising efficacy in uveal melanoma

The objective response rate following a single infusion of anzu-cel was 67% and the disease control rate was 88%. All responses were partial and lasted for a median of 11 months.

The median progression-free survival (PFS) was 8.5 months and the median overall survival (OS) was not reached. The 6- and 12-month PFS rates were 69% and 39%, respectively, while the 12-month OS rate was 71%.

“Our takeaway is that targeting a highly expressed antigen, in this case PRAME, with [TCR]-specific T cells even in a cold tumor like uveal melanoma can result in clinical activity, and this can be taken forward in other areas of oncology,” concluded Patel.

“These results are being verified in a phase 2 extension cohort in uveal melanoma.”

First phase 1 trial to be presented at a Presidential Session

The discussant John Haanen, from the Netherlands Cancer Institute in Amsterdam, sought to explain why these early results merited inclusion in a Presidential Session. He pointed out that patients with metastatic uveal melanoma “have a very dismal outcome and cure in this patient population is extremely rare.”

Haanen added that although tebentafusp is approved for HLA-A*02:01-positive disease, “we don’t know whether we are really curing patients with this treatment.” And although immune checkpoint inhibitors are often used, they “are largely ineffective,” he said.

In this setting, the 67% response rate with anzu-cel stands out, continued the discussant, but he is not yet convinced that anzu-cel will lead to cures and awaits more data.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature

ESMO Congress 2025; Berlin, Germany: 17–21 October